NPHP1

Summary

NPHP1 (nephrocystin 1, HGNC:7905) is a protein-coding gene on chromosome 2q13, encoding Nephrocystin-1 (O15259). Together with BCAR1 it may play a role in the control of epithelial cell polarity.

This gene encodes a protein with src homology domain 3 (SH3) patterns. This protein interacts with Crk-associated substrate, and it appears to function in the control of cell division, as well as in cell-cell and cell-matrix adhesion signaling, likely as part of a multifunctional complex localized in actin- and microtubule-based structures. Mutations in this gene cause familial juvenile nephronophthisis type 1, a kidney disorder involving both tubules and glomeruli. Defects in this gene are also associated with Senior-Loken syndrome type 1, also referred to as juvenile nephronophthisis with Leber amaurosis, which is characterized by kidney and eye disease, and with Joubert syndrome type 4, which is characterized by cerebellar ataxia, oculomotor apraxia, psychomotor delay and neonatal breathing abnormalities, sometimes including retinal dystrophy and renal disease. Multiple transcript variants encoding different isoforms have been found for this gene.

Source: NCBI Gene 4867 — RefSeq curated summary.

At a glance

• Gene–disease (curated): nephronophthisis 1 (Definitive, ClinGen) — +3 more curated relationships
• Clinical variants (ClinVar): 1,059 total — 86 pathogenic, 62 likely-pathogenic
• Phenotypes (HPO): 155
• Dosage sensitivity (ClinGen): haploinsufficiency autosomal recessive, triplosensitivity no evidence
• MANE Select transcript: NM_001128178

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:7905
Approved symbol	NPHP1
Name	nephrocystin 1
Location	2q13
Locus type	gene with protein product
Status	Approved
Aliases	JBTS4, SLSN1
Ensembl gene	ENSG00000144061
Ensembl biotype	protein_coding
OMIM	607100
Entrez	4867

Gene structure

Transcript identifiers

Ensembl transcripts: 25 — 15 protein_coding, 9 retained_intron, 1 nonsense_mediated_decay

ENST00000316534, ENST00000355301, ENST00000393272, ENST00000417665, ENST00000418527, ENST00000422492, ENST00000445609, ENST00000449600, ENST00000461707, ENST00000493051, ENST00000496524, ENST00000674677, ENST00000675067, ENST00000675294, ENST00000675356, ENST00000675632, ENST00000675752, ENST00000676028, ENST00000676053, ENST00000676091, ENST00000676165, ENST00000676258, ENST00000866172, ENST00000955859, ENST00000955860

RefSeq mRNA: 6 — MANE Select: NM_001128178 NM_000272, NM_001128178, NM_001128179, NM_001374256, NM_001374257, NM_207181

CCDS: CCDS2086, CCDS46384, CCDS46385, CCDS46386

Canonical transcript exons

ENST00000445609 — 20 exons

Exon	Start	End
ENSE00000000326	110123348	110124063
ENSE00001402584	110164688	110164730
ENSE00001413137	110163048	110163135
ENSE00001514680	110204900	110205013
ENSE00003469878	110129186	110129259
ENSE00003479922	110169806	110169998
ENSE00003484426	110146753	110146835
ENSE00003496507	110161603	110161697
ENSE00003520903	110178423	110178547
ENSE00003521141	110165052	110165155
ENSE00003529827	110179624	110179684
ENSE00003547185	110131679	110131791
ENSE00003565868	110150182	110150256
ENSE00003575009	110147916	110148026
ENSE00003602075	110144493	110144569
ENSE00003633314	110125637	110125681
ENSE00003636110	110201421	110201494
ENSE00003637191	110168452	110168553
ENSE00003645138	110143542	110143641
ENSE00003654056	110160127	110160255

Expression profiles

Bgee: expression breadth ubiquitous, 193 present calls, max score 93.38.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 6.0093 / max 117.7866, expressed in 1464 samples.

FANTOM5 promoters (2 alternative TSS)

Promoter ID	TPM avg	Samples expressed
30120	5.7447	1453
30119	0.2647	106

Top tissues by expression

275 total, by Bgee expression score (0-100, higher = more expressed):

Tissue	Anatomy ID	Expression score	Quality
right uterine tube	UBERON:0001302	93.38	gold quality
bronchial epithelial cell	CL:0002328	90.87	gold quality
olfactory segment of nasal mucosa	UBERON:0005386	90.61	gold quality
hindlimb stylopod muscle	UBERON:0004252	89.31	gold quality
left testis	UBERON:0004533	89.04	gold quality
right testis	UBERON:0004534	88.73	gold quality
testis	UBERON:0000473	87.28	gold quality
adenohypophysis	UBERON:0002196	85.93	gold quality
buccal mucosa cell	CL:0002336	85.85	gold quality
muscle of leg	UBERON:0001383	85.51	gold quality
primordial germ cell in gonad	CL:0000670 ∩ UBERON:0000991	85.20	gold quality
gastrocnemius	UBERON:0001388	84.86	gold quality
male germ line stem cell (sensu Vertebrata) in testis	CL:0000089 ∩ UBERON:0000473	84.69	gold quality
pituitary gland	UBERON:0000007	84.41	gold quality
calcaneal tendon	UBERON:0003701	84.26	gold quality
epithelium of bronchus	UBERON:0002031	82.58	gold quality
bronchus	UBERON:0002185	81.81	gold quality
right lobe of thyroid gland	UBERON:0001119	81.47	gold quality
left lobe of thyroid gland	UBERON:0001120	81.24	gold quality
thyroid gland	UBERON:0002046	80.35	gold quality
mucosa of paranasal sinus	UBERON:0005030	79.92	gold quality
muscle organ	UBERON:0001630	79.84	gold quality
sural nerve	UBERON:0015488	79.07	gold quality
metanephros cortex	UBERON:0010533	78.90	gold quality
oocyte	CL:0000023	78.76	gold quality
tendon	UBERON:0000043	78.52	gold quality
body of uterus	UBERON:0009853	78.20	gold quality
lower esophagus muscularis layer	UBERON:0035833	77.83	gold quality
lower esophagus	UBERON:0013473	77.82	gold quality
right adrenal gland cortex	UBERON:0035827	77.74	gold quality

Single-cell (SCXA)

Detected in 3 experiment(s), a significant marker in 3.

Experiment	Marker?	Max mean expression
E-CURD-114	yes	12.12
E-ANND-3	yes	11.30
E-MTAB-9388	yes	7.05

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

30 targeting NPHP1, top 30 by miRDB confidence (max_score; target_count = how many genes the miRNA targets in total — lower means more specific):

miRNA	Max score	Avg score	miRNA target_count
HSA-MIR-4282	99.99	75.36	6408
HSA-MIR-548AW	99.99	72.57	3559
HSA-MIR-568	99.98	69.86	2084
HSA-MIR-6753-3P	99.93	66.57	637
HSA-MIR-7107-3P	99.93	66.73	627
HSA-MIR-450B-5P	99.92	71.48	3175
HSA-MIR-518A-5P	99.70	69.01	2209
HSA-MIR-527	99.70	69.01	2209
HSA-MIR-452-5P	99.65	69.63	1762
HSA-MIR-4676-3P	99.65	69.31	1733
HSA-MIR-892C-3P	99.65	69.38	1745
HSA-MIR-3609	99.52	69.89	2587
HSA-MIR-548AH-5P	99.52	69.73	2626
HSA-MIR-513A-3P	99.39	70.63	3620
HSA-MIR-513C-3P	99.39	70.63	3620
HSA-MIR-32-3P	99.36	68.20	2517
HSA-MIR-20B-3P	99.29	67.05	784
HSA-MIR-4721	99.26	66.05	818
HSA-MIR-3606-3P	99.11	69.84	3254
HSA-MIR-877-3P	99.09	68.10	1637
HSA-MIR-374A-3P	98.87	67.82	1531
HSA-MIR-6512-5P	98.76	69.29	1195
HSA-MIR-218-1-3P	98.63	67.97	832
HSA-MIR-5094	98.63	67.11	1062
HSA-MIR-6881-3P	98.04	68.24	1777
HSA-MIR-3137	97.26	66.78	761
HSA-MIR-6759-3P	96.94	68.31	823
HSA-MIR-382-5P	96.71	65.90	762
HSA-MIR-584-5P	95.82	68.05	848
HSA-MIR-217-3P	95.67	68.42	1000

Functional genomics

ClinGen dosage: haploinsufficiency 30 (autosomal recessive), triplosensitivity 0 (no evidence). ClinGen Gene Dosage Map

Literature-anchored findings (GeneRIF, showing 39)

• NPHP1 gene deletion associated with juvenile nephronophthisis is present in a subset of individuals with Joubert syndrome (PMID:15138899)
• part of multifunctional complex localized in actin- and microtubule-based structures (PMID:15661758)
• casein kinase 2 induces PACS-1 binding of nephrocystin and targeting to cilia (PMID:16308564)
• A premature stop codon, 1756C>T, at R586 in 4 patients was associated with an NPHP-1 deletion in 2 pts and with a 1122+2 duplication in one. The duplication had a low probablilty of maintaining the splicing effect on this obligatory donor splice site. (PMID:16762963)
• NPHP1 gene deletion associated with juvenile nephronophthisis is present in a subset of individuals with Joubert syndrome (PMID:16782989)
• Nephrocystin deficiency or dysfunction at the transition zone of renal monocilia and the photoreceptor connecting cilium might explain renal failure and retinal degeneration that are observed in patients with NPHP1. (PMID:16885411)
• Epistatic effects that are provided by heterozygous NPHP6 and AHI1 mutations and variants may contribute to the appearance of extrarenal symptoms in patients with NPHP1 mutations. (PMID:17409309)
• In six families with nephronophthisis, there were two mutations in either NPHP1, NPHP3, or NPHP4, suggesting oligogenicity. (PMID:17855640)
• These data define Ack1 as a novel interaction partner of nephrocystin-1 and implicate cell-cell junctions and the renal collecting duct in the pathology of nephronophthisis. (PMID:18477472)
• Jouberin interacts with nephrocystin-1 in HEK293 cells (PMID:18633336)
• Alternative splicing of ADAM15 regulates its interactions with cellular SH3 proteins SNX33 and nephrocystin (PMID:19718658)
• PC-1 polyproline motif interacts with the SH3 domain of NPHP1. (PMID:20856870)
• NPHP1 deletion analysis should always be considered in patients with apparently dominant nephronophthisis. (PMID:21258817)
• Nephrocystin-4 regulates Pyk2-induced tyrosine phosphorylation of nephrocystin-1 to control targeting to monocilia (PMID:21357692)
• NPHP1 genetic testing is important to diagnose patients with nephronophthisis, familial juvenile disease. (PMID:22523277)
• Plk1 colocalizes with nephrocystin-1 and induces it’s phosphorylation in the transition zone of primary cilia in epithelial cells. (PMID:22701722)
• Prevalence and incidence estimation of large NPHP1 homozygous deletion in Tunisian patients with clinical pictures of tubulo-interstitiel kidney disorder and chronic renal failure. (PMID:22743096)
• Report NPHP1 mutations in nephronophthisis and associated ciliopathies and Joubert syndrome-related disorders. (PMID:22982934)
• Congenital ocular motor apraxia and Joubert syndrome found to have a compound heterozygous mutation in the NPHP1 gene that is responsible for juvenile nephronophthisis type 1. (PMID:23683649)
• These results suggest that NPHP1 mutations are probably rare primary causes of Bardet-Biedl syndrome that contribute to the mutational burden of the disorder. (PMID:24746959)
• We report the unexpectedly common retinal involvement of NPHP type 1 with an additional MALL deletion in a Korean cohort. (PMID:25401970)
• A homozygous deletion was identified in the NPHP1 gene spanning at least from exon 5 to exon 20 in two families in Iranian children with nephronophthisis. (PMID:25851290)
• Copy number variation analysis of the NPHP1 gene using the commercially available MLPA kit identified a recurrent large homozygous deletion encompassing all NPHP1 exons. (PMID:26037636)
• associated with male factor infertility (PMID:26198798)
• dynamic genomic rearrangements occurred historically within the NPHP1 locus and generated SV haplotypes observed in the human population today, which may confer differential susceptibility to genomic instability and the NPHP1 deletion (PMID:26641089)
• Ocular motor apraxia (OMA) may present with extraocular manifestations (nephronophthisis and cerebellar vermis hypoplasia) and that OMA can be associated with NPHP1 mutations. (PMID:27316287)
• we are the first to show in a large cohort that NPH due to NPHP1 homozygous full gene deletions has a prevalence of one in 200 patients (0.5%) in all adult-onset ESRD. (PMID:29654215)
• Genetic screening of 6 patients with suspected NPHP causing chronic renal failure belonging to 6 families identified in 2/6 patients a deletion of exons 5-7-20 and in 4/6 patients an heterozygous deletion of exon 20 and an heterozygous deletion on exon 17 not yet described in literature. (PMID:29786190)
• Report renal pathology in series of patients with nephronophthisis due to NPHP1 gene deletion. (PMID:29949740)
• The genetic investigation revealed a novel homozygous nonsense mutation, p. E697X,37 and a novel homozygous missense mutation, p. F691 L, in the NPHP1 gene. His parents and fraternal twin harbored heterozygous mutations of the two loci and had no renal symptoms. His elder sister developed ESRD and died at 23 years of age. CONCLUSIONS: The report indicated that adult NPHP should be taken into consideration for adults with (PMID:31096956)
• Copy-number variation of the NPHP1 gene in patients with juvenile Nephronophthisis. (PMID:31402777)
• Clinical and pathological features and varied mutational spectra of pathogenic genes in 55 Chinese patients with nephronophthisis. (PMID:32173348)
• Homozygous full gene deletion of the NPHP1 gene was identified in a Chinese family with NPHP, which was the molecular pathogenic basis of this disorder. (PMID:32306954)
• SENIOR-LOKEN SYNDROME: A Case Series and Review of the Renoretinal Phenotype and Advances of Molecular Diagnosis. (PMID:33512896)
• NPHP1 gene-associated nephronophthisis is associated with an occult retinopathy. (PMID:34153329)
• An Nphp1 knockout mouse model targeting exon 2-20 demonstrates characteristic phenotypes of human nephronophthisis. (PMID:34415307)
• Scalp Tumor and Hydroureteronephrosis in Patients with Nephronophthisis and Homozygous NPHP1 Deletion. (PMID:36942623)
• A case report of two Chinese monozygotic twins with NPHP1 gene-associated nephronophthisis undergoing kidney transplantation from a related living-donor. (PMID:36948406)
• [C/EBPbeta mediates expressions of downstream inflammatory factors of the tumor necrosis factor-alpha signaling pathway in renal tubular epithelial cells with NPHP1 knockdown]. (PMID:38293987)

Cross-species orthologs

4 orthologs

Organism	Symbol	Gene ID
danio_rerio	nphp1	ENSDARG00000009046
mus_musculus	Nphp1	ENSMUSG00000027378
rattus_norvegicus	Nphp1	ENSRNOG00000015756
caenorhabditis_elegans		WBGENE00010898

Protein

Protein identifiers

Nephrocystin-1 — O15259 (reviewed: O15259)

Alternative names: Juvenile nephronophthisis 1 protein

All UniProt accessions (9): O15259, A0A6Q8PGI7, A0A6Q8PH10, A0A6Q8PHD4, A0A6Q8PHS3, C9J082, C9JNM7, H7C014, H7C2K4

UniProt curated annotations — full annotation on UniProt →

Function. Together with BCAR1 it may play a role in the control of epithelial cell polarity. Involved in the organization of apical junctions in kidney cells together with NPHP4 and RPGRIP1L/NPHP8. Does not seem to be strictly required for ciliogenesis. Seems to help to recruit PTK2B/PYK2 to cell matrix adhesions, thereby initiating phosphorylation of PTK2B/PYK2 and PTK2B/PYK2-dependent signaling. May play a role in the regulation of intraflagellar transport (IFT) during cilia assembly. Required for normal retina development. In connecting photoreceptor cilia influences the movement of some IFT proteins such as IFT88 and WDR19. Involved in spermatogenesis.

Subunit / interactions. Interacts with BCAR1, PTK2B/PYK2 and tensin. Interacts with INVS and NPHP3. Interacts with PACS1; the interaction is dependent on NPHP1 phosphorylation by CK2. Interacts with KIF7. Interacts with AHI1 and TNK2. Interacts with NPHP4 in a complex containing NPHP1, NPHP4 and RPGRIP1L. Interacts with IQCB1; the interaction likely requires additional interactors. Interacts with ANKS3. Interacts with SPATA7. Interacts with FLNA.

Subcellular location. Cell junction. Adherens junction. Cell projection. Cilium. Cytoplasm. Cytoskeleton. Cilium axoneme. Tight junction.

Tissue specificity. Widespread expression, with highest levels in pituitary gland, spinal cord, thyroid gland, testis, skeletal muscle, lymph node and trachea. Weakly expressed in heart, kidney and pancreas. Expressed in nasal epithelial cells (at protein level). Expressed in the renal collecting duct (at protein level).

Post-translational modifications. Phosphorylation by CK2 is required for the interaction with PACS1 and the targeting to the base region of cilia.

Disease relevance. Nephronophthisis 1 (NPHP1) [MIM:256100] An autosomal recessive inherited disease characterized by anemia, polyuria, polydipsia, isosthenuria and death in uremia. Symmetrical destruction of the kidneys involving both tubules and glomeruli occurs. The underlying pathology is a chronic tubulo-interstitial nephropathy with characteristic tubular basement membrane thickening and medullary cyst formation. Associations with extrarenal symptoms, especially ocular lesions, are frequent. The age at death ranges from about 4 to 15 years. The disease is caused by variants affecting the gene represented in this entry. Senior-Loken syndrome 1 (SLSN1) [MIM:266900] A renal-retinal disorder characterized by progressive wasting of the filtering unit of the kidney (nephronophthisis), with or without medullary cystic renal disease, and progressive eye disease. Typically this disorder becomes apparent during the first year of life. The disease is caused by variants affecting the gene represented in this entry. Joubert syndrome 4 (JBTS4) [MIM:609583] A disorder presenting with cerebellar ataxia, oculomotor apraxia, hypotonia, neonatal breathing abnormalities and psychomotor delay. Neuroradiologically, it is characterized by cerebellar vermian hypoplasia/aplasia, thickened and reoriented superior cerebellar peduncles, and an abnormally large interpeduncular fossa, giving the appearance of a molar tooth on transaxial slices (molar tooth sign). Additional variable features include retinal dystrophy and renal disease. Joubert syndrome type 4 is a phenotypically mild form. The disease is caused by variants affecting the gene represented in this entry.

Domain organisation. The SH3 domain mediates the stable interaction with Cas.

Miscellaneous. Nephronophthisis type 1 patients deficient for NPHP1 show normal overall integrity of respiratory cilia.

Similarity. Belongs to the nephrocystin-1 family.

Isoforms (4)

UniProt ID	Names	Canonical?
O15259-1	1, NPHP1	yes
O15259-2	2, NPHP1-8A
O15259-3	3
O15259-4	4

RefSeq proteins (6): NP_000263, NP_001121650, NP_001121651, NP_001361185, NP_001361186, NP_997064 (=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR001452	SH3_domain	Domain
IPR030642	NPHP1_SH3	Domain
IPR036028	SH3-like_dom_sf	Homologous_superfamily
IPR039687	NPHP1	Family

Pfam: PF00018

UniProt features (37 total): strand 7, modified residue 6, mutagenesis site 5, splice variant 4, helix 4, sequence variant 2, region of interest 2, coiled-coil region 2, compositionally biased region 2, chain 1, domain 1, turn 1

Structure

Experimental structures (PDB)

2 structures.

PDB	Method	Resolution (Å)
1S1N	SOLUTION NMR
6O1Q	SOLUTION NMR

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-O15259-F1	76.22	0.45

Functional residue map

Curated UniProt residues grouped by drug-discovery relevance — catalytic, ligand-binding, modification, and mutation-validated positions. Source: UniProtKB sequence features.

Post-translational modifications (6): 123, 126, 349, 721, 46, 121

Mutagenesis-validated functional residues (5):

Position	Phenotype
121	impairs interaction with pacs1; when associated with a-123 and a-126.
123	impairs interaction with pacs1; when associated with a-121 and a-126.
126	impairs interaction with pacs1; when associated with a-121 and a-123.
180	loss of sh3 domain fold.
203	does not affect fold stability, as assessed by circular dichroism thermal denaturation melting curves and by nmr spectro

Function

Pathways and Gene Ontology

Reactome pathways

1 pathways

ID	Pathway
R-HSA-5620912	Anchoring of the basal body to the plasma membrane

MSigDB gene sets: 436 (showing top): GSE45365_NK_CELL_VS_CD8A_DC_DN, GOBP_MORPHOGENESIS_OF_AN_EPITHELIUM, GOBP_EPITHELIUM_DEVELOPMENT, GOBP_BEHAVIOR, GOBP_PROTEIN_LOCALIZATION_TO_CILIUM, GRAESSMANN_APOPTOSIS_BY_SERUM_DEPRIVATION_DN, GOBP_APICAL_JUNCTION_ASSEMBLY, GOBP_REGULATION_OF_CELL_JUNCTION_ASSEMBLY, GOBP_MALE_GAMETE_GENERATION, GOBP_REGULATION_OF_CELLULAR_COMPONENT_BIOGENESIS, GOBP_CELL_CELL_ADHESION, GOBP_POSITIVE_REGULATION_OF_CELLULAR_COMPONENT_BIOGENESIS, GOBP_CELL_JUNCTION_ORGANIZATION, GOBP_POSITIVE_REGULATION_OF_CELL_JUNCTION_ASSEMBLY, GOBP_RESPONSE_TO_RADIATION

GO Biological Process (11): signal transduction (GO:0007165), visual behavior (GO:0007632), cell projection organization (GO:0030030), actin cytoskeleton organization (GO:0030036), spermatid differentiation (GO:0048515), retina development in camera-type eye (GO:0060041), protein localization involved in establishment of planar polarity (GO:0090251), cell-cell adhesion (GO:0098609), positive regulation of bicellular tight junction assembly (GO:1903348), spermatogenesis (GO:0007283), cell differentiation (GO:0030154)

GO Molecular Function (2): structural molecule activity (GO:0005198), protein binding (GO:0005515)

GO Cellular Component (13): cytoplasm (GO:0005737), cytosol (GO:0005829), cell-cell junction (GO:0005911), adherens junction (GO:0005912), bicellular tight junction (GO:0005923), cilium (GO:0005929), axoneme (GO:0005930), membrane (GO:0016020), motile cilium (GO:0031514), photoreceptor connecting cilium (GO:0032391), cytoskeleton (GO:0005856), cell projection (GO:0042995), anchoring junction (GO:0070161)

Reactome top-level categories

Rollup of top-1 pathways:

Category	Pathways
Assembly of the 9+0 primary cilium	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cellular anatomical structure	5
developmental process involved in reproduction	2
cell communication	1
cellular process	1
signaling	1
regulation of cellular process	1
cellular response to stimulus	1
behavior	1
response to light stimulus	1
cellular component organization	1
cytoskeleton organization	1
actin filament-based process	1
spermatogenesis	1
cellular process involved in reproduction in multicellular organism	1
cell differentiation	1
camera-type eye development	1
anatomical structure development	1
establishment of planar polarity	1
intracellular protein localization	1
cell adhesion	1
bicellular tight junction assembly	1
positive regulation of cell junction assembly	1
regulation of bicellular tight junction assembly	1
male gamete generation	1
cellular developmental process	1
molecular_function	1
binding	1
intracellular anatomical structure	1
cytoplasm	1
anchoring junction	1
cell-cell junction	1
apical junction complex	1
tight junction	1
intraciliary transport particle	1
membrane-bounded organelle	1
plasma membrane bounded cell projection	1
cytoskeleton	1
microtubule	1
ciliary plasm	1
cilium	1

Protein interactions and networks

STRING

2121 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
NPHP1	NPHP4	O75161	999
NPHP1	RPGRIP1L	Q68CZ1	993
NPHP1	TMEM67	Q5HYA8	992
NPHP1	AHI1	Q8N157	991
NPHP1	NPHP3	Q7Z494	983
NPHP1	CEP290	O15078	975
NPHP1	MKS1	Q9NXB0	960
NPHP1	INVS	Q9Y283	950
NPHP1	CC2D2A	Q9P2K1	948
NPHP1	TMEM216	Q9P0N5	940
NPHP1	IQCB1	Q15051	934
NPHP1	B9D1	Q9UPM9	927
NPHP1	RPGRIP1	Q96KN7	906
NPHP1	B9D2	Q9BPU9	886
NPHP1	TMEM231	Q9H6L2	879

IntAct

53 interactions, top by confidence:

A	B	Type	Score
NPHP1	NPHP4	psi-mi:“MI:2364”(proximity)	0.930
NPHP4	NPHP1	psi-mi:“MI:0915”(physical association)	0.930
NPHP1	NPHP4	psi-mi:“MI:0915”(physical association)	0.930
NPHP4	NPHP1	psi-mi:“MI:0914”(association)	0.930
NPHP1	NPHP4	psi-mi:“MI:0914”(association)	0.930
ADAM15	NPHP1	psi-mi:“MI:0407”(direct interaction)	0.710
NPHP1	ADAM15	psi-mi:“MI:0915”(physical association)	0.710
ADAM15	NPHP1	psi-mi:“MI:0915”(physical association)	0.710
DNAJC7	PLD2	psi-mi:“MI:0914”(association)	0.640
RPGR	NPHP1	psi-mi:“MI:0915”(physical association)	0.560
RPGR	NPHP1	psi-mi:“MI:0914”(association)	0.560
NPHP1	PKD1	psi-mi:“MI:0407”(direct interaction)	0.560
KCNA5	TMEM223	psi-mi:“MI:0914”(association)	0.530
AHI1	NPHP1	psi-mi:“MI:0915”(physical association)	0.520
NPHP1	AHI1	psi-mi:“MI:0915”(physical association)	0.520

BioGRID (128): NPHP1 (Proximity Label-MS), AGK (Proximity Label-MS), ATP2B1 (Proximity Label-MS), BAIAP2L1 (Proximity Label-MS), BCAS3 (Proximity Label-MS), TMEM256 (Proximity Label-MS), CACYBP (Proximity Label-MS), CBL (Proximity Label-MS), CEP170 (Proximity Label-MS), CHTOP (Proximity Label-MS), CLTC (Proximity Label-MS), COPA (Proximity Label-MS), DBT (Proximity Label-MS), DNM2 (Proximity Label-MS), DNMBP (Proximity Label-MS)

ESM2 similar proteins: A0A5F9C6I2, A1L3F5, B0I564, B1AY13, D3ZXK7, F8VPU6, O15259, O15327, O17482, O95876, P21359, P49021, P50851, P97526, Q04690, Q2HJ90, Q3B7T1, Q4KM95, Q4QQM5, Q4R4D7, Q5R9R1, Q5RA60, Q5U1Z0, Q5XPI3, Q5XPI4, Q62717, Q6GLR7, Q6GQV7, Q6P4S8, Q6VNB8, Q7TMY8, Q7Z494, Q7Z6Z7, Q86UW7, Q8BYR5, Q8IY22, Q8IZQ1, Q8N201, Q8NAN2, Q8NEN0

Diamond homologs: A1C4A5, A6SED8, A7EK16, A8PWF6, F1LM93, O15259, O42287, O43125, O43586, P05433, P07947, P09324, P13115, P17713, P29355, P41239, P42680, P42681, P42682, P42686, P42690, P46108, P46109, P47941, P62993, P62994, P87378, P87379, P97814, Q04929, Q08012, Q13588, Q1JPZ3, Q4P3H6, Q5R4J7, Q5U2U2, Q60631, Q63768, Q64010, Q66II3

SIGNOR signaling

7 interactions.

A	Effect	B	Mechanism
CSNK2A1	up-regulates	NPHP1	phosphorylation
PTK2B	“up-regulates activity”	NPHP1	phosphorylation
SRC	“up-regulates activity”	NPHP1	phosphorylation

Disease & clinical

Clinical variants and AI predictions

ClinVar

1059 variants total. Per-class counts are floors (≥ shown; pagination cap):

Classification	Count (floor)
Pathogenic	86
Likely pathogenic	62
Uncertain significance	393
Likely benign	382
Benign	49

Top pathogenic / likely-pathogenic (30)

Variant ID	HGVS	Classification
1030710	NM_001128178.3(NPHP1):c.1588C>T (p.Arg530Ter)	Pathogenic
1072531	NC_000002.11:g.(?110879913)(110963639_?)del	Pathogenic
1076772	NM_001128178.3(NPHP1):c.1270-1G>A	Pathogenic
1179110	GRCh37/hg19 2q13(chr2:110880925-110962590)	Pathogenic
1179212	GRCh37/hg19 2q13(chr2:110880893-110962659)	Pathogenic
1338365	NM_001128178.3(NPHP1):c.143+1G>A	Pathogenic
1344621	NM_001128178.3(NPHP1):c.1636del (p.Ser546fs)	Pathogenic
1402007	NM_001128178.3(NPHP1):c.1493_1494del (p.Leu498fs)	Pathogenic
1415124	NM_001128178.3(NPHP1):c.812_813insA (p.Pro272fs)	Pathogenic
1427636	NM_001128178.3(NPHP1):c.1412del (p.Pro471fs)	Pathogenic
1437615	NM_001128178.3(NPHP1):c.937del (p.Asp313fs)	Pathogenic
1444725	NM_001128178.3(NPHP1):c.1130del (p.Lys377fs)	Pathogenic
1451354	NM_001128178.3(NPHP1):c.844C>T (p.Gln282Ter)	Pathogenic
1452271	NC_000002.11:g.(?110881368)(110959091_?)del	Pathogenic
1709559	NM_001128178.3(NPHP1):c.480dup (p.Gly161fs)	Pathogenic
1943039	NM_001128178.3(NPHP1):c.739del (p.His247fs)	Pathogenic
1993329	NM_001128178.3(NPHP1):c.16C>T (p.Gln6Ter)	Pathogenic
2019744	NM_001128178.3(NPHP1):c.1064_1080del (p.Leu354_Cys355insTer)	Pathogenic
2037917	NM_001128178.3(NPHP1):c.64C>T (p.Gln22Ter)	Pathogenic
2079871	NM_001128178.3(NPHP1):c.1246_1252del (p.Leu416fs)	Pathogenic
2115519	NM_001128178.3(NPHP1):c.1628_1635del (p.Ser543fs)	Pathogenic
2190054	NM_001128178.3(NPHP1):c.77dup (p.Ser26fs)	Pathogenic
2203131	NM_001128178.3(NPHP1):c.84_87del (p.Ser29fs)	Pathogenic
224960	NM_000272.3(NPHP1):c.(?-1)(*1_?)del	Pathogenic
242361	2q13 deletion (290 kb)	Pathogenic
2444262	NM_001128178.3(NPHP1):c.625-1G>A	Pathogenic
253441	GRCh37/hg19 2q13(chr2:110881237-110963848)x1	Pathogenic
2578903	GRCh37/hg19 2q13(chr2:110881368-110962545)x0	Pathogenic
2677261	NM_001128178.3(NPHP1):c.625-2A>G	Pathogenic
2677262	NM_001128178.3(NPHP1):c.882C>A (p.Tyr294Ter)	Pathogenic

SpliceAI

3410 predictions. Top by Δscore:

Variant	Effect	Δscore
2:110129144:T:TA	donor_gain	1.0000
2:110129184:AC:A	donor_gain	1.0000
2:110129185:CC:C	donor_gain	1.0000
2:110131674:CTTA:C	donor_loss	1.0000
2:110131675:TTAC:T	donor_loss	1.0000
2:110131676:TACCA:T	donor_loss	1.0000
2:110131677:A:AC	donor_gain	1.0000
2:110131678:C:CC	donor_gain	1.0000
2:110131678:C:CT	donor_loss	1.0000
2:110131744:A:T	acceptor_gain	1.0000
2:110131787:GTAGA:G	acceptor_gain	1.0000
2:110131788:TAGA:T	acceptor_gain	1.0000
2:110131789:AGA:A	acceptor_gain	1.0000
2:110131790:GA:G	acceptor_gain	1.0000
2:110131792:C:CC	acceptor_gain	1.0000
2:110131794:A:C	acceptor_gain	1.0000
2:110131795:T:C	acceptor_gain	1.0000
2:110131795:T:TC	acceptor_gain	1.0000
2:110143537:CCCA:C	donor_loss	1.0000
2:110143538:CCA:C	donor_loss	1.0000
2:110143539:CACCT:C	donor_loss	1.0000
2:110143540:A:C	donor_loss	1.0000
2:110143541:C:G	donor_loss	1.0000
2:110143642:C:CC	acceptor_gain	1.0000
2:110143643:T:C	acceptor_gain	1.0000
2:110143645:T:TC	acceptor_gain	1.0000
2:110144487:CCATA:C	donor_loss	1.0000
2:110144488:CATAC:C	donor_loss	1.0000
2:110144489:ATAC:A	donor_loss	1.0000
2:110144490:TA:T	donor_loss	1.0000

AlphaMissense

4456 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
2:110150248:G:C	S419R	0.996
2:110150248:G:T	S419R	0.996
2:110150250:T:G	S419R	0.996
2:110150199:A:G	W436R	0.995
2:110150199:A:T	W436R	0.995
2:110146809:G:C	S487R	0.994
2:110146809:G:T	S487R	0.994
2:110146811:T:G	S487R	0.994
2:110143590:A:G	L549P	0.993
2:110160152:C:G	R408P	0.993
2:110146802:A:G	W490R	0.992
2:110146802:A:T	W490R	0.992
2:110146804:C:T	G489D	0.991
2:110150249:C:A	S419I	0.991
2:110178465:A:G	L96P	0.991
2:110160147:A:G	C410R	0.990
2:110163082:G:C	F330L	0.990
2:110163082:G:T	F330L	0.990
2:110163084:A:G	F330L	0.990
2:110178477:A:G	L92P	0.988
2:110147950:A:T	I467K	0.987
2:110160145:A:C	C410W	0.987
2:110163083:A:G	F330S	0.987
2:110168471:A:T	V202D	0.987
2:110150191:A:C	F438L	0.986
2:110150191:A:T	F438L	0.986
2:110150193:A:G	F438L	0.986
2:110143590:A:T	L549H	0.985
2:110150228:G:T	A426D	0.985
2:110150245:G:C	N420K	0.985

dbSNP variants (sampled 300 via entrez): RS1000014121 (2:110138936 T>A,C), RS1000024613 (2:110187659 A>G), RS1000041421 (2:110179172 G>A), RS1000084553 (2:110173489 A>G), RS1000092618 (2:110130060 G>A), RS1000160828 (2:110153341 A>G), RS1000242739 (2:110192977 G>A,C), RS1000277088 (2:110151972 C>T), RS1000285782 (2:110201623 G>A,T), RS1000286899 (2:110152221 C>T), RS1000295079 (2:110193192 A>C,G), RS1000322287 (2:110137493 C>A,T), RS1000339778 (2:110145271 C>T), RS1000464764 (2:110129781 T>A), RS1000524439 (2:110124501 A>C)

Disease associations

OMIM: gene MIM:607100 | disease phenotypes: MIM:256100, MIM:266900, MIM:609583, MIM:209900, MIM:213300, MIM:300958, MIM:610805, MIM:204000

GenCC curated gene-disease

Disease	Classification	Inheritance
Joubert syndrome with renal defect	Definitive	Autosomal recessive
nephronophthisis 1	Definitive	Autosomal recessive
Bardet-Biedl syndrome	Supportive	Autosomal recessive
Senior-Loken syndrome	Supportive	Autosomal recessive

ClinGen Gene-Disease Validity (1)

Expert-panel classifications — Definitive > Strong > Moderate > Limited > Disputed > Refuted.

Disease	Classification	Inheritance
nephronophthisis 1	Definitive	AR

Mondo (15): nephronophthisis (MONDO:0019005), nephronophthisis 1 (MONDO:0009728), Senior-Loken syndrome 1 (MONDO:0009962), Joubert syndrome with renal defect (MONDO:0012308), Bardet-Biedl syndrome 1 (MONDO:0008854), focal segmental glomerulosclerosis (MONDO:0100313), Joubert syndrome 1 (MONDO:0008944), intellectual disability, X-linked 102 (MONDO:0010497), congenital anomaly of kidney and urinary tract (MONDO:0019719), inherited retinal dystrophy (MONDO:0019118), Leber congenital amaurosis (MONDO:0018998), Joubert syndrome and related disorders (MONDO:0015369), kidney disorder (MONDO:0005240), Bardet-Biedl syndrome (MONDO:0015229), Senior-Loken syndrome (MONDO:0017842)

Orphanet (10): Nephronophthisis (Orphanet:655), Joubert syndrome with renal defect (Orphanet:220497), Senior-Loken syndrome (Orphanet:3156), Juvenile nephronophthisis (Orphanet:93592), X-linked intellectual disability-hypotonia-movement disorder syndrome (Orphanet:457260), Renal or urinary tract malformation (Orphanet:93545), OBSOLETE: Inherited retinal disorder (Orphanet:71862), Leber congenital amaurosis (Orphanet:65), Joubert syndrome and related disorders (Orphanet:140874), Bardet-Biedl syndrome (Orphanet:110)

HPO phenotypes

155 total (30 of 155 shown, HPO-id order):

HPO	Term
HP:0000007	Autosomal recessive inheritance
HP:0000011	Neurogenic bladder
HP:0000028	Cryptorchidism
HP:0000076	Vesicoureteral reflux
HP:0000083	Renal insufficiency
HP:0000085	Horseshoe kidney
HP:0000090	Nephronophthisis
HP:0000092	Renal tubular atrophy
HP:0000100	Nephrotic syndrome
HP:0000103	Polyuria
HP:0000108	Renal corticomedullary cysts
HP:0000112	Nephropathy
HP:0000119	Abnormality of the genitourinary system
HP:0000126	Hydronephrosis
HP:0000135	Hypogonadism
HP:0000147	Polycystic ovaries
HP:0000163	Abnormal oral cavity morphology
HP:0000175	Cleft palate
HP:0000202	Orofacial cleft
HP:0000218	High palate
HP:0000238	Hydrocephalus
HP:0000276	Long face
HP:0000278	Retrognathia
HP:0000316	Hypertelorism
HP:0000343	Long philtrum
HP:0000358	Posteriorly rotated ears
HP:0000365	Hearing impairment
HP:0000388	Otitis media
HP:0000400	Macrotia
HP:0000426	Prominent nasal bridge

GWAS associations

0 associations (top):

MeSH disease descriptors (10)

Descriptor	Name	Tree numbers
D020788	Bardet-Biedl Syndrome	C10.228.140.617.200; C11.270.684.624; C16.131.077.245.125; C16.320.184.125
D005923	Glomerulosclerosis, Focal Segmental	C12.050.351.968.419.570.363.640; C12.200.777.419.570.363.660; C12.950.419.570.363.640
D007674	Kidney Diseases	C12.050.351.968.419; C12.200.777.419; C12.950.419
D057130	Leber Congenital Amaurosis	C11.270.516; C11.768.364
D058499	Retinal Dystrophies	C11.768.585.658
C537909	Bardet-Biedl syndrome 1 (supp.)
C566906	Cakut (supp.)
C536296	Joubert syndrome 4 (supp.)
C537699	Nephronophthisis, familial juvenile (supp.)
C537580	Senior Loken Syndrome (supp.)

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

PharmGKB: 1 entry (VIP=true, CPIC=false)

CTD chemical–gene interactions

28 total (human), top 28 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
Tobacco Smoke Pollution	decreases expression	2
aristolochic acid I	decreases expression	1
methylmercuric chloride	decreases expression	1
bisphenol A	affects cotreatment, decreases methylation	1
terbufos	increases methylation	1
trichostatin A	affects expression	1
tris(1,3-dichloro-2-propyl)phosphate	decreases expression	1
CGP 52608	affects binding, increases reaction	1
2-palmitoylglycerol	increases expression	1
Sunitinib	decreases expression	1
Fulvestrant	affects cotreatment, decreases methylation	1
Vorinostat	increases expression	1
Air Pollutants	increases abundance, increases expression	1
Azacitidine	increases expression	1
Benzo(a)pyrene	increases methylation	1
Bucladesine	increases expression, affects cotreatment	1
Fonofos	increases methylation	1
Estradiol	affects cotreatment, increases expression	1
Methotrexate	increases expression	1
Methyl Methanesulfonate	increases expression	1
Parathion	increases methylation	1
Smoke	increases abundance, increases expression	1
Testosterone	decreases expression	1
Thimerosal	increases expression	1
Cyclosporine	decreases expression	1
Aflatoxin B1	decreases methylation	1
Medroxyprogesterone Acetate	affects cotreatment, increases expression	1
Antirheumatic Agents	increases expression	1

Cellosaurus cell lines

7 cell lines: 7 induced pluripotent stem cell

First 10 cell lines (id-ordered, not curated):

Cellosaurus	Name	Category	Sex
CVCL_D0NH	UCSFi001-A-68	Induced pluripotent stem cell	Male
CVCL_ZB54	HPS0446	Induced pluripotent stem cell	Female
CVCL_ZB55	HPS0447	Induced pluripotent stem cell	Female
CVCL_ZB56	HPS0448	Induced pluripotent stem cell	Female
CVCL_ZE68	HPS0449	Induced pluripotent stem cell	Male
CVCL_ZE69	HPS0450	Induced pluripotent stem cell	Male
CVCL_ZE70	HPS0451	Induced pluripotent stem cell	Male

Clinical trials (associated diseases)

307 trials via MONDO — disease-level, not drug-specific.

Trial	Phase	Status	Title
NCT01129557	PHASE4	TERMINATED	Aldosterone Breakthrough During Diovan, Tekturna, and Combination Therapy in Patients With Proteinuric Kidney Disease
NCT02399462	PHASE4	WITHDRAWN	Acthar for Treatment of Post-transplant FSGS
NCT02585804	PHASE4	COMPLETED	Treating to Reduce Albuminuria and Normalize Hemodynamic Function in Focal ScLerosis With dApagliflozin Trial Effects
NCT02633046	PHASE4	COMPLETED	Acthar for Treatment-Resistant or Treatment-Intolerant Proteinuria
NCT07219121	PHASE4	RECRUITING	Sparsentan in Posttransplant Immunoglobulin A Nephropathy or Focal Segmental Glomerulosclerosis
NCT00067990	PHASE4	COMPLETED	Angiotensin II Blockade for Chronic Allograft Nephropathy
NCT00117078	PHASE4	COMPLETED	Aranesp® Monthly Preference Study - 2
NCT00117130	PHASE4	COMPLETED	Study to Evaluate Effectiveness of Aranesp®
NCT00132431	PHASE4	COMPLETED	START: Sensipar Treatment Algorithm to Reach K/DOQI Targets in Chronic Kidney Disease Subjects With Secondary Hyperparathyroidism
NCT00140985	PHASE4	COMPLETED	Antiproteinuric Efficacy of Losartan Potassium in Patients With Non-Diabetic Proteinuric Renal Diseases (0954-213)
NCT00246129	PHASE4	COMPLETED	CamTac Trial:Campath-Tacrolimus vs IL2R MoAb/Tacrolimus/MMF in Renal Transplantation
NCT00275535	PHASE4	COMPLETED	The Comparison of Tacrolimus and Sirolimus Immunosuppression Based Drug Regimens in Kidney Transplant Recipients
NCT00282217	PHASE4	COMPLETED	Study Evaluating Sirolimus in the Treatment of Kidney Transplant
NCT00289614	PHASE4	COMPLETED	Patients With Renal Impairment and Diabetes Undergoing Computed Tomography (CT)
NCT00290069	PHASE4	UNKNOWN	Renal Function Optimization With Mycophenolate Mofetil (MMF) Immunosuppressor Regimes (ALHAMBRA)
NCT00338468	PHASE4	TERMINATED	A Study to Assess Disability in Anemic Elderly Patients With Kidney Disease Receiving PROCRIT (Epoetin Alfa)
NCT00368901	PHASE4	COMPLETED	STAAR-2 Clinical Study
NCT00369733	PHASE4	COMPLETED	STAAR-3 Clinical Study
NCT00369772	PHASE4	COMPLETED	STAAR-1 Clinical Study
NCT00379899	PHASE4	COMPLETED	ADVANCE: Study to Evaluate Cinacalcet Plus Low Dose Vitamin D on Vascular Calcification in Subjects With Chronic Kidney Disease Receiving Hemodialysis
NCT00443508	PHASE4	UNKNOWN	Reduction or Discontinuation of CNI’s With Conversion to Everolimus-Based Immunosuppresion
NCT00452478	PHASE4	TERMINATED	Conversion From Standard Phosphate Binder Therapy to Fosrenol® (Lanthanum Carbonate) in Chronic Kidney Disease Stage 5
NCT00492518	PHASE4	COMPLETED	Acetylcysteine, Theophylline, and a Combination of Both in the Prophylaxis of Contrast-Induced Nephropathy
NCT00505102	PHASE4	UNKNOWN	Safe Renal Function In Long Term Heart Transplanted Patients
NCT00526331	PHASE4	COMPLETED	Evaluation of Arterial Pressure Based Cardiac Output for Goal-Directed Perioperative Therapy
NCT00688480	PHASE4	COMPLETED	Do Xanthine Oxidase Inhibitors Reduce Both Left Ventricular Hypertrophy and Endothelial Dysfunction in Cardiovascular Patients With Renal Dysfunction?
NCT00863707	PHASE4	COMPLETED	A Study of the Safety and Tolerance of Regadenoson in Subjects With Renal Impairment
NCT01101698	PHASE4	UNKNOWN	Vitamin K2 and Vessel Calcification in Chronic Kidney Disease Patients
NCT01150201	PHASE4	COMPLETED	Aliskiren Combined With Losartan in Proteinuric, Non-diabetic Chronic Kidney Disease
NCT01155141	PHASE4	COMPLETED	Idiopathic Focal Segmental Glomerulosclerosis (FSGS) and Treatment With ACTH
NCT01228279	PHASE4	COMPLETED	Sympathetic Activity in Patients With End-stage Renal Disease on Peritoneal Dialysis
NCT01334333	PHASE4	COMPLETED	Comparison of Medication Adherence Between Once and Twice Daily Tacrolimus in Stable Renal Transplant Recipients
NCT01437943	PHASE4	TERMINATED	Effect of Short Term Aliskiren Treatment in Kidney Transplant Patients
NCT01545479	PHASE4	COMPLETED	Increased Renal Oxygenation and Angiotensin Converting Enzyme Inhibition
NCT01614431	PHASE4	COMPLETED	N Acetyl Cysteine for Cystinosis Patients
NCT01631149	PHASE4	COMPLETED	Effect of Deep BLock on Intraoperative Surgical Conditions
NCT01722513	PHASE4	UNKNOWN	Efficacy and Safety of Alprostadil Prevent Contrast Induced Nephropathy
NCT01985360	PHASE4	COMPLETED	ISCHEMIA-Chronic Kidney Disease Trial
NCT02311010	PHASE4	UNKNOWN	Practical Use of Advagraf de Novo After Kidney Transplantation According to Recipient Genetic Polymorphism
NCT02413073	PHASE4	COMPLETED	Whole Body Vibration in Kidney Disease